当前位置：
X-MOL 学术
›
J. Med. Chem.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Design, Synthesis, and Biological Evaluation of the Third Generation 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl)carboxamido]morphinan (NAP) Derivatives as μ/κ Opioid Receptor Dual Selective Ligands
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-01-04 00:00:00 , DOI: 10.1021/acs.jmedchem.8b01158 Yi Zheng 1 , Samuel Obeng 1 , Huiqun Wang 1 , Abdulmajeed M. Jali 2 , Bharath Peddibhotla 1 , Dwight A. Williams 1 , Chuanchun Zou 1 , David L. Stevens 2 , William L. Dewey 2 , Hamid I. Akbarali 2 , Dana E. Selley 2 , Yan Zhang 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-01-04 00:00:00 , DOI: 10.1021/acs.jmedchem.8b01158 Yi Zheng 1 , Samuel Obeng 1 , Huiqun Wang 1 , Abdulmajeed M. Jali 2 , Bharath Peddibhotla 1 , Dwight A. Williams 1 , Chuanchun Zou 1 , David L. Stevens 2 , William L. Dewey 2 , Hamid I. Akbarali 2 , Dana E. Selley 2 , Yan Zhang 1
Affiliation
|
μ opioid receptor (MOR) agonists have been widely applied for treating moderate to severe pain. However, numerous adverse effects have been associated with their application, including opioid-induced constipation (OIC), respiratory depression, and addiction. On the basis of previous work in our laboratory, NAP, a 6β-N-4′-pyridyl substituted naltrexamine derivative, was identified as a peripheral MOR antagonist that may be used to treat OIC. To further explore its structure–activity relationship, a new series of NAP derivatives were designed, synthesized, and biologically evaluated. Among these derivatives, NFP and NYP significantly antagonized the antinociception effect of morphine. Whereas NAP acted mainly peripherally, its derivatives NFP and NYP actually can act centrally. Furthermore, NFP produced significantly lesser withdrawal symptoms than naloxone at similar doses. These results suggest that NFP has the potential to be a lead compound to treat opioid abuse and addiction.
中文翻译：
作为μ/κ阿片受体双重受体的第三代17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[（4'-吡啶基）羧酰胺基]吗啡喃（NAP）衍生物的设计，合成和生物学评估选择性配体
μ阿片受体（MOR）激动剂已广泛应用于治疗中度至重度疼痛。但是，其应用已引起许多不良反应，包括阿片类药物引起的便秘（OIC），呼吸抑制和成瘾。根据我们实验室NAP先前的工作，一个6β- N-4'-吡啶基取代的纳曲胺衍生物被鉴定为可用于治疗OIC的外周MOR拮抗剂。为了进一步探索其结构-活性关系，设计，合成了一系列新的NAP衍生物，并对其进行了生物学评估。在这些衍生物中，NFP和NYP显着拮抗吗啡的抗伤害感受作用。NAP主要在外围起作用，而其衍生产品NFP和NYP实际上可以在中心起作用。此外，在相似剂量下，NFP产生的戒断症状明显少于纳洛酮。这些结果表明，NFP有潜力成为治疗阿片类药物滥用和成瘾的先导化合物。
更新日期：2019-01-04
中文翻译：
作为μ/κ阿片受体双重受体的第三代17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[（4'-吡啶基）羧酰胺基]吗啡喃（NAP）衍生物的设计，合成和生物学评估选择性配体
μ阿片受体（MOR）激动剂已广泛应用于治疗中度至重度疼痛。但是，其应用已引起许多不良反应，包括阿片类药物引起的便秘（OIC），呼吸抑制和成瘾。根据我们实验室NAP先前的工作，一个6β- N-4'-吡啶基取代的纳曲胺衍生物被鉴定为可用于治疗OIC的外周MOR拮抗剂。为了进一步探索其结构-活性关系，设计，合成了一系列新的NAP衍生物，并对其进行了生物学评估。在这些衍生物中，NFP和NYP显着拮抗吗啡的抗伤害感受作用。NAP主要在外围起作用，而其衍生产品NFP和NYP实际上可以在中心起作用。此外，在相似剂量下，NFP产生的戒断症状明显少于纳洛酮。这些结果表明，NFP有潜力成为治疗阿片类药物滥用和成瘾的先导化合物。
京公网安备 11010802027423号